PROJECT ABSTRACT Acute lung injury within 72 hours of lung transplantation, termed Primary Graft Dysfunction (PGD), is a major cause of early post-transplant morbidity and mortality. PGD results in increased healthcare costs and poor functional outcomes for lung allograft recipients. Importantly, PGD is also a risk factor for developing Bronchiolitis Obliterans Syndrome, the main cause of late graft failure and death in this population. Therapeutic strategies aimed at ameliorating PGD may extend post-transplant allograft and patient survival. However, the pathophysiologic mechanisms regulating PGD remain poorly understood, and additional experimental studies are needed to identify novel approaches for therapeutic modulation. Ischemia-reperfusion injury is a major determinant of PGD, and is associated with activation of pro-inflammatory signaling pathways initiated by toll- like receptors. Toll-like receptors 2 and 4 recognize damage-associated molecular patterns released by sterile tissue injury, which have been reported in serum and bronchoalveolar lavage fluid of human lung transplant recipients. Accordingly, we hypothesize that lung ischemia-reperfusion injury releases endogenous damage-associated molecular patterns, which promote PGD through activation of toll-like receptors. Using a novel mouse orthotopic lung transplant model that replicates the physiologic, histopathologic and immunologic features of human PGD, we will test this hypothesis with two specific aims: 1) Characterize the role of toll-like receptors 2 and 4 in ischemia-reperfusion-induced lung graft injury, and 2) Characterize the role of damage-associated molecular patterns in ischemia-reperfusion-induced lung graft injury. Collectively, the studies proposed here are aimed at generating new insight into the pathophysiology of PGD and identifying potential pharmacologic targeting strategies for treating PGD in the context of a mentored career development plan. My long-term goal is to become an academic pulmonologist with a research focus in transplant immunobiology. The mentoring, training and support facilitated by this K08 career development award will enable me to acquire the training and expertise necessary for translating novel findings in experimental models to therapeutic strategies for treating lung allograft injury and rejection in humans. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Primary graft dysfunction is the major cause of early morbidity and mortality following lung transplantation, and has been associated with an increased risk for developing bronchiolitis obliterans syndrome and late graft failure. This project will investigate the role of innate immune signaling pathways in regulating primary graft dysfunction using a novel mouse model. We aim to identify potential pharmacologic targeting strategies for treating primary graft dysfunction and improving post-lung transplant outcomes. )